Summary Human intestinal tract is colonized by diverse microbial communities, termed the microbiota. Microbiota plays an important role in educating the immune system. However, the nature of the microbe-host interactions that help maintain immune homeostasis is poorly understood. One feature of the gut microbiota is the formation of multicellular communities, termed biofilms, in the mucus layer. The formation of biofilms is accompanied by the release of bacterial products that form an extracellular matrix. Amyloid fibers are an important extracellular matrix component of biofilms formed by diverse groups of bacteria, including many members of the Proteobacteria, Bacteroidia and Firmicutes. Conserved beta sheet structure of amyloid fibers is recognized by receptors of the innate immune system as a conserved molecular pattern (i.e. a so-called pathogen-associated molecular pattern or PAMP). However, it is not known whether detection of amyloid fibrils by the innate immune system represents one of the elusive microbe-host interactions that contribute to immune homeostasis at the mucosal surface. In addition to amyloids, extracellular bacterial DNA (eDNA) has been shown to be present in several bacterial biofilms. The objective of this application is to determine the mechanisms by which bacterial amyloid curli/DNA complexes are recognized by the immune system in the gut. We hypothesize that the immune system recognizes bacterial amyloid curli/DNA complexes as conserved molecules common to bacterial biofilms. Curli/DNA complex acts by accessing multiple cellular compartments and activates multiple PRRs including TLR2, TLR9 and NLRP3 leading to epithelial barrier reinforcement in the gut by the generation of immunomodulatory cytokines, IL-10 and IL- 18.